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Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury
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Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (14 May 2018) | Viewed by 156443

Special Issue Editor

Prof. Dr. Joan Roselló-Catafau

E-Mail Website
Guest Editor
Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain
Interests: organ (liver, pancreas, small intestine, kidney) transplantation; cell signaling molecular mechanisms in organ transplantation; graft therapeutics; preservation and preservation solutions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ischemia-reperfusion injury (IRI) is an inherent syndrome associated with liver surgery and organ transplantation. IRI is responsible for the graft rejection that occurs after one week of transplantation (TX), and its necessary to prevent it to avoid further organ re-transplantations. The advances in the pathophysiology mechanisms of ischemia reperfusion are poor when compared to the development of immunosuppressive strategies in TX. This is the reason why it is necessary to explore new insights on the molecular pathways involved in the complex pathophysiology of IRI, covering different perspectives, including different organs (heart, liver, kidney, pancreas, small intestine) with a special emphasis on the underlying pathophysiological mechanisms, including the involvement of inflammatory mediators, mitochondrial dysfunction, and apoptosis and other potential markers associated with IRI. Pathophysiological mechanisms will be explored under normo-thermic conditions (warm ischemia-reperfusion) or transplantation (cold ischemia reperfusion) in order to prevent deleterious injury due to ischemia (oxygen deprivation) and reperfusion (blood/oxygen restoration). These therapeutic strategies include pharmacological treatments with natural or synthetic drugs, as well as protective, surgical ones, such as ischemia and post-conditioning, respectively. In liver transplantation, ischemic injury of the graft during cold storage (“static preservation”) is mitigated by using organ preservation solutions, which can be supplemented with additives to increase graft preservation. Recently, new machine perfusion strategies (“dynamic preservation”) are primarily used to preserve kidneys and livers for transplantation purposes. Protection mechanisms in dynamic are not always established.

This Special Issue calls for original research, mini and full reviews, and perspectives that address the progress and current knowledge on the pathophysiological mechanisms of IRI in different organs, such as heart, liver, pancreas, kidney, and small intestine. This includes therapeutic pharmacological strategies, as well as and protective surgical interventions, such as ischemic preconditioning/postconditioning) to prevent IRI in warm and cold ischemia-reperfusion models. Contributions are not limited to the fields that are mentioned in the keywords.

Prof. Dr. Joan Rosello-Catafau
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ischemia-reperfusion injury (heart, liver, pancreas, kidney, intestine)
  • organ transplantation
  • static cold storage and dynamic graft preservation
  • inflammation/apoptosis mediators
  • mithochondrial disfunction and related markers.
  • pharmacological strategies to prevent IRI
  • ischemic preconditioning and postconditiong

Published Papers (25 papers)

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Editorial

Jump to: Research, Review

4 pages, 192 KiB  
Editorial
Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury
by Arnau Panisello-Roselló and Joan Roselló-Catafau
Int. J. Mol. Sci. 2018, 19(12), 4093; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124093 - 18 Dec 2018
Cited by 16 | Viewed by 3818
Abstract
Ischemia-reperfusion injury (IRI) is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)

Research

Jump to: Editorial, Review

13 pages, 3145 KiB  
Article
Aldehyde Dehydrogenase 2 (ALDH2) in Rat Fatty Liver Cold Ischemia Injury
by Arnau Panisello-Roselló, Norma Alva, Marta Flores, Alexandre Lopez, Carlos Castro Benítez, Emma Folch-Puy, Anabela Rolo, Carlos Palmeira, René Adam, Teresa Carbonell and Joan Roselló-Catafau
Int. J. Mol. Sci. 2018, 19(9), 2479; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092479 - 22 Aug 2018
Cited by 21 | Viewed by 4887
Abstract
Institut George Lopez-1 (IGL-1) and Histidine-tryptophan-ketoglutarate (HTK) solutions are proposed as alternatives to UW (gold standard) in liver preservation. Their composition differs in terms of the presence/absence of oncotic agents such as HES or PEG, and is decisive for graft conservation before transplantation. [...] Read more.
Institut George Lopez-1 (IGL-1) and Histidine-tryptophan-ketoglutarate (HTK) solutions are proposed as alternatives to UW (gold standard) in liver preservation. Their composition differs in terms of the presence/absence of oncotic agents such as HES or PEG, and is decisive for graft conservation before transplantation. This is especially so when fatty (steatotic) livers are used since these grafts are more vulnerable to ischemia insult during conservation. Their composition determines the extent of the subsequent reperfusion injury after transplantation. Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, has been reported to play a protective role in warm ischemia-reperfusion injury (IRI), but its potential in fatty liver cold ischemic injury has not yet been investigated. We evaluated the relevance of ALDH2 activity in cold ischemia injury when fatty liver grafts from Zucker Obese rats were preserved in UW, HTK, and IGL-1 solutions, in order to study the mechanisms involved. ALDH2 upregulation was highest in livers preserved in IGL-1. It was accompanied by a decrease in transaminases, apoptosis (Caspase 3 and TUNEL assay), and lipoperoxidation, which was concomitant with the effective clearance of toxic aldehydes such as 4-hydroxy-nonenal. Variations in ATP levels were also determined. The results were consistent with levels of NF-E2 p45-related factor 2 (Nrf2), an antioxidant factor. Here we report for the first time the relevance of mitochondrial ALDH2 in fatty liver cold preservation and suggest that ALDH2 could be considered a potential therapeutic target or regulator in clinical transplantation. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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12 pages, 5582 KiB  
Article
Glycocalyx Preservation and NO Production in Fatty Livers—The Protective Role of High Molecular Polyethylene Glycol in Cold Ischemia Injury
by Alexandre Lopez, Arnau Panisello-Rosello, Carlos Castro-Benitez and René Adam
Int. J. Mol. Sci. 2018, 19(8), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082375 - 12 Aug 2018
Cited by 19 | Viewed by 3550
Abstract
Improving the protection of marginal liver grafts during static cold storage is a major hurdle to increase the donor pool of organs. The endothelium glycocalyx quality of preservation influences future inflammatory and oxidative responses. One cellular pathway responsible for the formation of nitric [...] Read more.
Improving the protection of marginal liver grafts during static cold storage is a major hurdle to increase the donor pool of organs. The endothelium glycocalyx quality of preservation influences future inflammatory and oxidative responses. One cellular pathway responsible for the formation of nitric oxide by endothelial cells is dependent on the stimulation of proteoglycans present in the glycocalyx. We investigated the impact of the glycocalyx preservation in static cold storage of fatty liver preserved in different preservation solutions on the endothelium-mediated production of NO. Zucker fatty rat livers were preserved 24 h in static cold storage in either Institut Georges Lopez-1 (IGL-1) (n = 10), IGL-0 (i.e., without PEG35) (n = 5) or Histidine-Tryptophan-Ketoglutarate (HTK) (n = 10) preservation solutions before being processed for analysis. For Sham group (n = 5), the fatty livers were immediately analyzed after procurement. The level of transaminases and nitrites/nitrates were measured in the washing perfusate. Glycocalyx proteins expressions, Syndecan-1, glypican-1 and heparan sulfate (HS), were determined in the tissue (ELISA). Steatotic livers preserved 24 h in IGL-1 preservation solution have a significant lower level of transaminases (aspartate aminotransferase (AST), alanine aminotransferase (ALT)) and less histological damages than steatotic livers preserved 24 h with HTK (p = 0.0152). The syndecan-1 is significantly better preserved in IGL-1 group compared to HTK (p < 0.0001) and we observed the same tendency compared to IGL-0. No significant differences were observed with glypican-1. HS expression in HTK group was significantly higher compared to the three other groups. HS level in IGL-1 was even lower than IGL-0 (p = 0.0005) which was similar to Sham group. The better protection of the glycocalyx proteins in IGL-1 group was correlated with a higher production of NO than HTK (p = 0.0055) or IGL-0 (p = 0.0433). IGL-1 protective mechanisms through the formation of NO could be due to its better protective effects on the glycocalyx during SCS compared to other preservation solutions. This beneficial effect could involve the preservation state of syndecan-1 and the internalization of HS. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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12 pages, 12371 KiB  
Article
cPKCγ-Modulated Sequential Reactivation of mTOR Inhibited Autophagic Flux in Neurons Exposed to Oxygen Glucose Deprivation/Reperfusion
by Rongrong Hua, Song Han, Nan Zhang, Qingqing Dai, Ting Liu and Junfa Li
Int. J. Mol. Sci. 2018, 19(5), 1380; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051380 - 06 May 2018
Cited by 24 | Viewed by 4763
Abstract
We have reported that conventional protein kinase Cγ (cPKCγ)-modulated neuron-specific autophagy improved the neurological outcome of mice following ischemic stroke through the Akt-mechanistic target of rapamycin (mTOR) pathway. However, its detailed molecular mechanism remains unclear. In this study, primary cortical neurons from postnatal [...] Read more.
We have reported that conventional protein kinase Cγ (cPKCγ)-modulated neuron-specific autophagy improved the neurological outcome of mice following ischemic stroke through the Akt-mechanistic target of rapamycin (mTOR) pathway. However, its detailed molecular mechanism remains unclear. In this study, primary cortical neurons from postnatal one-day-old C57BL/6J cPKCγ wild-type (cPKCγ+/+) and knockout (cPKCγ−/−) mice suffering oxygen glucose deprivation/reperfusion (OGD/R) were used to simulate ischemia/reperfusion injury in vitro. A block of autophagic flux was observed in cPKCγ+/+ neurons under OGD/R exposure, characterized by accumulation of p62. Immunofluorescent results showed a decrease in colocalization between LC3 and Atg14 or Stx17 in cPKCγ+/+ neurons when compared with cPKCγ−/− neurons after OGD/R. However, the colocalization between LC3 and Lamp2 was barely decreased, indicating the presence of autolysosomes. The larger lysotracker-positive structures were also significantly increased. These results suggest that cPKCγ-induced inhibition of autophagy occurred at the stages of autophagosome formation, Stx17 anchoring, and the degradation of autolysosomes in particular. In addition, cPKCγ-modulated phosphorylation of mTOR at Ser 2481 was dependent on the site of Ser 2448, which may have blocked autophagic flux. cPKCγ-modulated sequential reactivation of mTOR inhibited autophagic flux in neurons exposed to OGD/R, which may provide endogenous interventional strategies for stroke, especially ischemia/reperfusion injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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13 pages, 15795 KiB  
Article
Preconditioning-Like Properties of Short-Term Hypothermia in Isolated Perfused Rat Liver (IPRL) System
by Norma Alva, Raquel G. Bardallo, David Basanta, Jesús Palomeque and Teresa Carbonell
Int. J. Mol. Sci. 2018, 19(4), 1023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041023 - 29 Mar 2018
Cited by 10 | Viewed by 3456
Abstract
Hypothermia may attenuate the progression of ischemia-induced damage in liver. Here, we determined the effects of a brief cycle of hypothermic preconditioning applied before an ischemic/reperfusion (I/R) episode in isolated perfused rat liver (IPRL) on tissue damage and oxidative stress. Rats (male, 200–250 [...] Read more.
Hypothermia may attenuate the progression of ischemia-induced damage in liver. Here, we determined the effects of a brief cycle of hypothermic preconditioning applied before an ischemic/reperfusion (I/R) episode in isolated perfused rat liver (IPRL) on tissue damage and oxidative stress. Rats (male, 200–250 g) were anaesthetised with sodium pentobarbital (60 mg·kg−1 i.p) and underwent laparatomy. The liver was removed and perfused in a temperature-regulated non-recirculating system. Livers were randomly divided into two groups (n = 6 each group). In the hypothermia-preconditioned group, livers were perfused with hypothermic buffer (cycle of 10 min at 22 °C plus 10 min at 37 °C) and the other group was perfused at 37 °C. Both groups were then submitted to 40 min of warm ischemia and 20 min of warm reperfusion. The level of tissue-damage indicators (alanine amino transferase, ALT; lactate dehydrogenase, LDH; and proteins), oxidative stress markers (thiobarbituric acid-reactive substances, TBARS; advanced oxidation protein products, AOPP; and glutathione, GSH) were measured in aliquots of perfusate sampled at different time intervals. Histological determinations and oxidative stress biomarkers in homogenized liver (AOPP; TBARS; nitric oxide derivatives, NOx; GSH and glutathione disulphide, GSSG) were also made in the tissue at the end. Results showed that both damage and oxidant indicators significantly decreased while antioxidant increased in hypothermic preconditioned livers. In addition, homogenized liver determinations and histological observations at the end of the protocol corroborate the results in the perfusate, confirming the utility of the perfusate as a non-invasive method. In conclusion, hypothermic preconditioning attenuates oxidative damage and appears to be a promising strategy to protect the liver against IR injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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12 pages, 3577 KiB  
Article
Endogenous Selenoprotein P, a Liver-Derived Secretory Protein, Mediates Myocardial Ischemia/Reperfusion Injury in Mice
by Hiroshi Chadani, Soichiro Usui, Oto Inoue, Takashi Kusayama, Shin-ichiro Takashima, Takeshi Kato, Hisayoshi Murai, Hiroshi Furusho, Ayano Nomura, Hirofumi Misu, Toshinari Takamura, Shuichi Kaneko and Masayuki Takamura
Int. J. Mol. Sci. 2018, 19(3), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19030878 - 16 Mar 2018
Cited by 26 | Viewed by 4985
Abstract
Selenoprotein P (SeP), a liver-derived secretory protein, functions as a selenium supply protein in the body. SeP has been reported to be associated with insulin resistance in humans through serial analysis of gene expression. Recently, SeP has been found to inhibit vascular endothelial [...] Read more.
Selenoprotein P (SeP), a liver-derived secretory protein, functions as a selenium supply protein in the body. SeP has been reported to be associated with insulin resistance in humans through serial analysis of gene expression. Recently, SeP has been found to inhibit vascular endothelial growth factor-stimulated cell proliferation in human umbilical vein endothelial cells, and impair angiogenesis in a mouse hind limb model. In this study, the role of SeP in ischemia/reperfusion (I/R) injury has been investigated. SeP knockout (KO) and littermate wild-type (WT) mice were subjected to 30 min of myocardial ischemia followed by 24 h of reperfusion. The myocardial infarct area/area at risk (IA/AAR), evaluated using Evans blue (EB) and 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in SeP KO mice than in WT mice. The number of terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei was significantly lower in SeP KO mice than in WT mice. In addition, caspase-3 activation was reduced in SeP KO mice compared to that in WT mice. Furthermore, phosphoinositide 3-kinase/Akt and Erk levels were examined for the reperfusion injury salvage kinase (RISK) pathway. Interestingly, SeP KO significantly increased the phosphorylation of IGF-1, Akt, and Erk compared to that in WT mice after I/R. Finally, I/R-induced myocardial IA/AAR was significantly increased in SeP KO mice overexpressing SeP in the liver compared to other SeP KO mice. These results, together, suggest that inhibition of SeP protects the heart from I/R injury through upregulation of the RISK pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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15 pages, 24789 KiB  
Article
Protective Effects of Olive Leaf Extract on Acrolein-Exacerbated Myocardial Infarction via an Endoplasmic Reticulum Stress Pathway
by Yuyu Xu, Lixing Wu, Aochang Chen, Chaoqi Xu and Qing Feng
Int. J. Mol. Sci. 2018, 19(2), 493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020493 - 07 Feb 2018
Cited by 23 | Viewed by 4641
Abstract
Many studies reported that air pollution particulate matter (PM) exposure was associated with myocardial infarction (MI). Acrolein representing the unsaturated aldehydes, the main component of PM, derives from the incomplete combustion of wood, plastic, fossil fuels and the main constitute of cigarette smoking. [...] Read more.
Many studies reported that air pollution particulate matter (PM) exposure was associated with myocardial infarction (MI). Acrolein representing the unsaturated aldehydes, the main component of PM, derives from the incomplete combustion of wood, plastic, fossil fuels and the main constitute of cigarette smoking. However, the effect of acrolein on MI remains not that clear. In the current study, the effect of acrolein-exacerbated MI was investigated. In vivo, male Sprague–Dawley rats received olive leaf extract (OLE) followed by acrolein, then isoprenaline (ISO) was received by subcutaneous injection to induce MI. Results showed that the expression levels of GRP78 and CHOP, two major components of endoplasmic reticulum (ER) stress were higher in the combination of acrolein and ISO than those in ISO treatment. The apoptosis marker, Bax, was also higher while the anti-apoptosis indicator, Bcl2 expression was lower both at protein and mRNA levels in the combination group. Also, the acrolein-protein adducts and myocardial pathological damage increased in the combination of acrolein and ISO relative to the ISO treatment. Besides, cardiac parameters, ejection fraction (EF) and fractional shortening (FS) were reduced more significantly when acrolein was added than in ISO treatment. Interestingly, all the changes were able to be ameliorated by OLE. Since hydroxytyrosol (HT) and oleuropein (OP) were the main components in OLE, we next investigated the effect of HT and OP on cardiomyocyte H9c2 cell apoptosis induced by acrolein through ER stress and Bax pathway. Results showed that GRP78, CHOP and Bax expression were upregulated, while Bcl2 expression was downregulated both at the protein and mRNA levels, when the H9c2 cells were treated with acrolein. In addition, pretreatment with HT can reverse the expression of GRP78, CHOP, Bax and Bcl2 on the protein and mRNA levels, while there was no effect of OP on the expression of GRP78 and CHOP on the mRNA levels. Overall, all these results demonstrated that OLE and the main components (HT and OP) could prevent the negative effects of acrolein on myocardium and cardiomyocytes. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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15 pages, 3927 KiB  
Article
In Vivo Evaluation of Cerebral Hemodynamics and Tissue Morphology in Rats during Changing Fraction of Inspired Oxygen Based on Spectrocolorimetric Imaging Technique
by Afrina Mustari, Takuya Kanie, Satoko Kawauchi, Shunichi Sato, Manabu Sato, Yasuaki Kokubo and Izumi Nishidate
Int. J. Mol. Sci. 2018, 19(2), 491; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020491 - 06 Feb 2018
Cited by 8 | Viewed by 4104
Abstract
During surgical treatment for cerebrovascular diseases, cortical hemodynamics are often controlled by bypass graft surgery, temporary occlusion of arteries, and surgical removal of veins. Since the brain is vulnerable to hypoxemia and ischemia, interruption of cerebral blood flow reduces the oxygen supply to [...] Read more.
During surgical treatment for cerebrovascular diseases, cortical hemodynamics are often controlled by bypass graft surgery, temporary occlusion of arteries, and surgical removal of veins. Since the brain is vulnerable to hypoxemia and ischemia, interruption of cerebral blood flow reduces the oxygen supply to tissues and induces irreversible damage to cells and tissues. Monitoring of cerebral hemodynamics and alteration of cellular structure during neurosurgery is thus crucial. Sequential recordings of red-green-blue (RGB) images of in vivo exposed rat brains were made during hyperoxia, normoxia, hypoxia, and anoxia. Monte Carlo simulation of light transport in brain tissue was used to specify relationships among RGB-values and oxygenated hemoglobin concentration (CHbO), deoxygenated hemoglobin concentration (CHbR), total hemoglobin concentration (CHbT), hemoglobin oxygen saturation (StO2), and scattering power b. Temporal courses of CHbO, CHbR, CHbT, and StO2 indicated physiological responses to reduced oxygen delivery to cerebral tissue. A rapid decrease in light scattering power b was observed after respiratory arrest, similar to the negative deflection of the extracellular direct current (DC) potential in so-called anoxic depolarization. These results suggest the potential of this method for evaluating pathophysiological conditions and loss of tissue viability. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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15 pages, 2132 KiB  
Article
The Optimal PEG for Kidney Preservation: A Preclinical Porcine Study
by Sebastien Giraud, Raphael Thuillier, Ricardo Codas, Emily Manguy, Benoit Barrou, Alexandre Valagier, Alexis Puichaud, Lionel Badet, Emmanuelle Nicolas, Michel Eugene and Thierry Hauet
Int. J. Mol. Sci. 2018, 19(2), 454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020454 - 03 Feb 2018
Cited by 12 | Viewed by 4097
Abstract
University of Wisconsin (UW) solution is not optimal for preservation of marginal organs. Polyethylene glycol (PEG) could improve protection. Similarly formulated solutions containing either 15 or 20 g/L PEG 20 kDa or 5, 15 and 30 g/L PEG 35 kDa were tested in [...] Read more.
University of Wisconsin (UW) solution is not optimal for preservation of marginal organs. Polyethylene glycol (PEG) could improve protection. Similarly formulated solutions containing either 15 or 20 g/L PEG 20 kDa or 5, 15 and 30 g/L PEG 35 kDa were tested in vitro on kidney endothelial cells, ex vivo on preserved kidneys, and in vivo in a pig kidney autograft model. In vitro, all PEGs provided superior preservation than UW in terms of cell survival, adenosine triphosphate (ATP) production, and activation of survival pathways. Ex vivo, tissue injury was lower with PEG 20 kDa compared to UW or PEG 35 kDa. In vivo, function recovery was identical between UW and PEG 35 kDa groups, while PEG 20 kDa displayed swifter recovery. At three months, PEG 35 kDa 15 and 30 g/L animals had worse outcomes than UW, while 5 g/L PEG 35 kDa was similar. PEG 20 kDa was superior to both UW and PEG 35 kDa in terms of function and fibrosis development, with low activation of damage pathways. PEG 20 kDa at 15 g/L was superior to 20 g/L. While in vitro models did not discriminate between PEGs, in large animal models of transplantation we showed that PEG 20 kDa offers a higher level of protection than UW and that longer chains such as PEG 35 kDa must be used at low doses, such as found in Institut George Lopez (IGL1, 1g/L). Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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13 pages, 2701 KiB  
Article
Cytoprotective Mechanisms in Fatty Liver Preservation against Cold Ischemia Injury: A Comparison between IGL-1 and HTK
by Arnau Panisello-Roselló, Eva Verde, Alexandre Lopez, Marta Flores, Emma Folch-Puy, Anabela Rolo, Carlos Palmeira, Georgina Hotter, Teresa Carbonell, René Adam and Joan Roselló-Catafau
Int. J. Mol. Sci. 2018, 19(2), 348; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020348 - 24 Jan 2018
Cited by 14 | Viewed by 5401
Abstract
Institute Goeorges Lopez 1 (IGL-1) and Histidine-Tryptophan-Ketoglutarate (HTK) preservation solutions are regularly used in clinical for liver transplantation besides University of Wisconsin (UW) solution and Celsior. Several clinical trials and experimental works have been carried out comparing all the solutions, however the comparative [...] Read more.
Institute Goeorges Lopez 1 (IGL-1) and Histidine-Tryptophan-Ketoglutarate (HTK) preservation solutions are regularly used in clinical for liver transplantation besides University of Wisconsin (UW) solution and Celsior. Several clinical trials and experimental works have been carried out comparing all the solutions, however the comparative IGL-1 and HTK appraisals are poor; especially when they deal with the underlying protection mechanisms of the fatty liver graft during cold storage. Fatty livers from male obese Zücker rats were conserved for 24 h at 4 °C in IGL-1 or HTK preservation solutions. After organ recovery and rinsing of fatty liver grafts with Ringer Lactate solution, we measured the changes in mechanistic target of rapamycin (mTOR) signaling activation, liver autophagy markers (Beclin-1, Beclin-2, LC3B and ATG7) and apoptotic markers (caspase 3, caspase 9 and TUNEL). These determinations were correlated with the prevention of liver injury (aspartate and alanine aminostransferase (AST/ALT), histology) and mitochondrial damage (glutamate dehydrogenase (GLDH) and confocal microscopy findings). Liver grafts preserved in IGL-1 solution showed a marked reduction on p-TOR/mTOR ratio when compared to HTK. This was concomitant with significant increased cyto-protective autophagy and prevention of liver apoptosis, including inflammatory cytokines such as HMGB1. Together, our results revealed that IGL-1 preservation solution better protected fatty liver grafts against cold ischemia damage than HTK solution. IGL-1 protection was associated with a reduced liver damage, higher induced autophagy and decreased apoptosis. All these effects would contribute to limit the subsequent extension of reperfusion injury after graft revascularization in liver transplantation procedures. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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16 pages, 3090 KiB  
Article
Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury
by Andrea Ferrigno, Clarissa Berardo, Laura Giuseppina Di Pasqua, Veronica Siciliano, Plinio Richelmi, Ferdinando Nicoletti and Mariapia Vairetti
Int. J. Mol. Sci. 2018, 19(2), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020314 - 23 Jan 2018
Cited by 14 | Viewed by 5220
Abstract
2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted [...] Read more.
2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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17 pages, 7105 KiB  
Article
Addition of Berberine to Preservation Solution in an Animal Model of Ex Vivo Liver Transplant Preserves Mitochondrial Function and Bioenergetics from the Damage Induced by Ischemia/Reperfusion
by Rui Miguel Martins, Anabela Pinto Rolo, João Soeiro Teodoro, Emanuel Furtado, Rui Caetano Oliveira, José Guilherme Tralhão and Carlos Marques Palmeira
Int. J. Mol. Sci. 2018, 19(1), 284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010284 - 19 Jan 2018
Cited by 16 | Viewed by 4127
Abstract
Liver transplantation is a therapeutic regimen to treat patients with non-malignant end-stage liver diseases and malignant tumors of hepatic origin. The ischemia/reperfusion (I/R) injury in liver transplantation is associated with disruption of mitochondrial function in the hepatic parenchyma. Several studies have been conducted [...] Read more.
Liver transplantation is a therapeutic regimen to treat patients with non-malignant end-stage liver diseases and malignant tumors of hepatic origin. The ischemia/reperfusion (I/R) injury in liver transplantation is associated with disruption of mitochondrial function in the hepatic parenchyma. Several studies have been conducted in animal models to identify pharmacological therapeutic strategies to minimize the injury induced by the cold/warm I/R in liver transplantation. Most of these studies were conducted in unrealistic conditions without the potential to be translated to clinical usage. Berberine (BBR) is a pharmacological compound with a potential protective effect of the mitochondrial function in the context of I/R. For the future clinical application of these pharmacological strategies, it is essential that a close resemblance exists between the methodology used in the animals models and real life. In this study, we have demonstrated that the addition of BBR to the preservation solution in an I/R setting preserves mitochondrial function and bioenergetics, protecting the liver from the deleterious effects caused by I/R. As such, BBR has the potential to be used as a pharmacological therapeutic strategy. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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11 pages, 1187 KiB  
Article
Pentoxifylline and Methylprednisolone Additively Alleviate Kidney Failure and Prolong Survival of Rats after Renal Warm Ischemia-Reperfusion
by Grzegorz Wystrychowski, Wojciech Wystrychowski, Władysław Grzeszczak, Andrzej Więcek, Robert Król and Antoni Wystrychowski
Int. J. Mol. Sci. 2018, 19(1), 221; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010221 - 11 Jan 2018
Cited by 9 | Viewed by 4774
Abstract
Renal ischemia-reperfusion injury (IRI) induces local inflammation leading to kidney damage. Since pentoxifylline (PTX) and steroids have distinct immunomodulatory properties, we aimed to evaluate for the first time their combined use in IRI-induced acute kidney injury (AKI) and chronic kidney disease (CKD) in [...] Read more.
Renal ischemia-reperfusion injury (IRI) induces local inflammation leading to kidney damage. Since pentoxifylline (PTX) and steroids have distinct immunomodulatory properties, we aimed to evaluate for the first time their combined use in IRI-induced acute kidney injury (AKI) and chronic kidney disease (CKD) in rats. In two experiments, PTX (100 mg/kg body weight subcutaneously) was administered 90 min prior to renal IRI or/and methylprednisolone (MP; 100 mg/kg body weight intramuscularly) was infused 60 min after reperfusion of a solitary kidney (AKI model: 45 min ischemia, 48 male Sprague-Dawley rats) or one kidney with excision of contralateral kidney 2 weeks later (CKD model: 90 min ischemia, 38 rats). Saline was infused in place of PTX or/and MP depending on the group. Renal function (diuresis, serum creatinine, creatinine clearance, sodium and potassium excretion, and urine protein/creatinine) was assessed at 48 h and 120 h post-IRI (AKI model) or 4, 16 and 24 weeks after IRI, along with survival analysis (CKD model). More evidently at early stages of AKI or CKD, treated animals showed higher glomerular filtration and diminished tubular loss of electrolytes, more so with PTX + MP than PTX or MP (serum creatinine (μmol/L) at 48 h of AKI: 60.9 ± 19.1 vs. 131.1 ± 94.4 vs. 233.4 ± 137.0, respectively, vs. 451.5 ± 114.4 in controls, all p < 0.05; and at 4 weeks of CKD: 89.0 ± 31.9 vs. 118.1 ± 64.5 vs. 156.9 ± 72.6, respectively, vs. 222.9 ± 91.4 in controls, p < 0.05 for PTX or PTX + MP vs. controls and PTX + MP vs. MP). Survival was better by >2-fold with PTX + MP (89%) vs. controls (40%; p < 0.05). PTX + MP largely protect from IRI-induced AKI and CKD and subsequent mortality in rats. This calls for clinical investigations, especially in kidney transplantation. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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5954 KiB  
Article
Liver Graft Susceptibility during Static Cold Storage and Dynamic Machine Perfusion: DCD versus Fatty Livers
by Andrea Ferrigno, Laura G. Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Barbara Mannucci, Plinio Richelmi, Anna Cleta Croce and Mariapia Vairetti
Int. J. Mol. Sci. 2018, 19(1), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010109 - 31 Dec 2017
Cited by 16 | Viewed by 6446
Abstract
We compared static preservation (cold storage, CS, 4 °C) with dynamic preservation (machine perfusion, MP, 20 °C) followed by reperfusion using marginal livers: a model of donation after cardiac death (DCD) livers and two models of fatty livers, the methionine-choline deficient (MCD) diet [...] Read more.
We compared static preservation (cold storage, CS, 4 °C) with dynamic preservation (machine perfusion, MP, 20 °C) followed by reperfusion using marginal livers: a model of donation after cardiac death (DCD) livers and two models of fatty livers, the methionine-choline deficient (MCD) diet model, and obese Zucker (fa/fa) rats. CS injury in DCD livers was reversed by an oxygenated washout (OW): hepatic damage, bile flow, and the ATP/ADP ratio in the OW + CS group was comparable with the ratio obtained with MP. Using fatty livers, CS preservation induced a marked release in hepatic and biliary enzymes in obese Zucker rats when compared with the MCD group. The same trend occurred for bile flow. No difference was found when comparing MP in MCD and obese Zucker rats. Fatty acid analysis demonstrated that the total saturated (SFA)/polyunsaturated fatty acid (PUFA) ratio was, respectively, 1.5 and 0.71 in obese Zucker and MCD rats. While preservation damage in DCD livers is associated with the ATP/ADP recovered with OW, injury in fatty livers is linked to fatty acid constituents: livers from obese. Zucker rats, with greater content in saturated FA, might be more prone to CS injury. On the contrary, MCD livers with elevated PUFA content might be less susceptible to hypothermia. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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2304 KiB  
Article
Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats
by Jung-Won Hwang, Young-Tae Jeon, Young-Jin Lim and Hee-Pyoung Park
Int. J. Mol. Sci. 2017, 18(11), 2347; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112347 - 06 Nov 2017
Cited by 36 | Viewed by 4942
Abstract
The anti-inflammatory actions of sevoflurane postconditioning are suggested as an important mechanism of sevoflurane postconditioning-induced neuroprotection against cerebral ischemia. Here, we determined whether the anti-inflammatory effects of sevoflurane postconditioning were mediated via inhibition of the toll-like receptor (TLR)-4/nuclear factor kappa B (NF-κB) pathway [...] Read more.
The anti-inflammatory actions of sevoflurane postconditioning are suggested as an important mechanism of sevoflurane postconditioning-induced neuroprotection against cerebral ischemia. Here, we determined whether the anti-inflammatory effects of sevoflurane postconditioning were mediated via inhibition of the toll-like receptor (TLR)-4/nuclear factor kappa B (NF-κB) pathway after global transient cerebral ischemia in rats. Forty-five rats were randomly assigned to five groups as follows: (1) control (10 min of ischemia, n = 10); (2) sevoflurane postconditioning (two periods of sevoflurane inhalation after ischemia for 10 min with a wash period of 10 min, n = 10); (3) resatorvid (intraperitoneal injection of a selective TLR-4 antagonist (3 mg/kg) 30 min before ischemia, n = 10); (4) sevoflurane postconditioning plus resatorvid (n = 10), and sham (n = 5). The numbers of necrotic and apoptotic cells in the hippocampal CA1 region, the expression levels of TLR-4, NF-κB, cleaved caspase-3, and tumor necrosis factor alpha (TNF-α) in the anterior part of each brain, and the serum levels of TNF-α, interleukin 6 (IL-6), and interleukin 1 beta (IL-1β) were assessed 1 day after ischemia. The necrotic cell counts and expression levels of TLR-4, NF-κB, caspase-3, and TNF-α in brain tissue as well as serum levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were significantly higher in the control group than in the other groups. Our findings suggest that the anti-inflammatory actions of sevoflurane postconditioning via inactivation of the TLR-4/NF-κB pathway and subsequent reduction in pro-inflammatory cytokine production, in part, contribute to sevoflurane postconditioning-induced neuroprotection after global transient cerebral ischemia in rats. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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Review

Jump to: Editorial, Research

15 pages, 648 KiB  
Review
Epithelial Cell Cycle Behaviour in the Injured Kidney
by Lies Moonen, Patrick C. D’Haese and Benjamin A. Vervaet
Int. J. Mol. Sci. 2018, 19(7), 2038; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19072038 - 13 Jul 2018
Cited by 47 | Viewed by 7151
Abstract
Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been [...] Read more.
Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-κβ) and p38-mitogen-activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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21 pages, 724 KiB  
Review
Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function
by Kelley Núñez, Paul Thevenot, Abeer Alfadhli and Ari Cohen
Int. J. Mol. Sci. 2018, 19(6), 1750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061750 - 13 Jun 2018
Cited by 13 | Viewed by 3914
Abstract
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation [...] Read more.
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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1 pages, 1250 KiB  
Review
Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver
by Weili Yang, Ji Chen, Yuhong Meng, Zhenzhen Chen and Jichun Yang
Int. J. Mol. Sci. 2018, 19(5), 1302; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051302 - 26 Apr 2018
Cited by 62 | Viewed by 8723
Abstract
Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, [...] Read more.
Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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14 pages, 678 KiB  
Review
The Costimulatory Pathways and T Regulatory Cells in Ischemia-Reperfusion Injury: A Strong Arm in the Inflammatory Response?
by Laura De Ramon, Jordi Guiteras, Roser Guiteras, Josep M. Cruzado, Josep M. Grinyó and Juan Torras
Int. J. Mol. Sci. 2018, 19(5), 1283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051283 - 25 Apr 2018
Cited by 6 | Viewed by 4564
Abstract
Costimulatory molecules have been identified as crucial regulators in the inflammatory response in various immunologic disease models. These molecules are classified into four different families depending on their structure. Here, we will focus on various ischemia studies that use costimulatory molecules as a [...] Read more.
Costimulatory molecules have been identified as crucial regulators in the inflammatory response in various immunologic disease models. These molecules are classified into four different families depending on their structure. Here, we will focus on various ischemia studies that use costimulatory molecules as a target to reduce the inherent inflammatory status. Furthermore, we will discuss the relevant role of T regulatory cells in these inflammatory mechanisms and the costimulatory pathways in which they are involved. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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26 pages, 1367 KiB  
Review
Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury—A Systematic Review of In Vivo Studies
by Aysun Tekbas, Jutta Huebner, Utz Settmacher and Uta Dahmen
Int. J. Mol. Sci. 2018, 19(4), 1085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041085 - 05 Apr 2018
Cited by 21 | Viewed by 4886
Abstract
Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of [...] Read more.
Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of common key pathways in ischemic liver and hepatotoxic injury results in oxidative stress, inflammatory responses and apoptosis causing organ damage. Controlling liver damage before and during surgery is essential for the postoperative outcome. Nigella sativa has a long tradition as a natural remedy. In the essential oil, Thymoquinone (TQ) was identified as the main component and responsible for most of the therapeutic effects. Therefore, this systematic review aimed to summarize the hepatoprotective effects of TQ and its potential suitability to improve surgical outcome by reducing surgical ischemic injury and hepatotoxicity of neoadjuvant chemotherapy. The key findings can be summarized as TQ having strong antioxidant, anti-inflammatory, antifibrotic, anti-/proapoptotic and anticarcinogenic effects. Almost no side effects were reported irrespective of a large dose range, suggesting a wide therapeutic window. These results give rise to the expectation that TQ could evolve to a novel powerful drug to reduce hepatic injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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20 pages, 499 KiB  
Review
Interplay between ROS and Antioxidants during Ischemia-Reperfusion Injuries in Cardiac and Skeletal Muscle
by Tingyang Zhou, Evan R. Prather, Davis E. Garrison and Li Zuo
Int. J. Mol. Sci. 2018, 19(2), 417; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020417 - 31 Jan 2018
Cited by 140 | Viewed by 8788
Abstract
Ischemia reperfusion (IR), present in myocardial infarction or extremity injuries, is a major clinical issue and leads to substantial tissue damage. Molecular mechanisms underlying IR injury in striated muscles involve the production of reactive oxygen species (ROS). Excessive ROS accumulation results in cellular [...] Read more.
Ischemia reperfusion (IR), present in myocardial infarction or extremity injuries, is a major clinical issue and leads to substantial tissue damage. Molecular mechanisms underlying IR injury in striated muscles involve the production of reactive oxygen species (ROS). Excessive ROS accumulation results in cellular oxidative stress, mitochondrial dysfunction, and initiation of cell death by activation of the mitochondrial permeability transition pore. Elevated ROS levels can also decrease myofibrillar Ca2+ sensitivity, thereby compromising muscle contractile function. Low levels of ROS can act as signaling molecules involved in the protective pathways of ischemic preconditioning (IPC). By scavenging ROS, antioxidant therapies aim to prevent IR injuries with positive treatment outcomes. Novel therapies such as postconditioning and pharmacological interventions that target IPC pathways hold great potential in attenuating IR injuries. Factors such as aging and diabetes could have a significant impact on the severity of IR injuries. The current paper aims to provide a comprehensive review on the multifaceted roles of ROS in IR injuries, with a focus on cardiac and skeletal muscle, as well as recent advancement in ROS-related therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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16 pages, 2096 KiB  
Review
Acute Limb Ischemia—Much More Than Just a Lack of Oxygen
by Florian Simon, Alexander Oberhuber, Nikolaos Floros, Albert Busch, Markus Udo Wagenhäuser, Hubert Schelzig and Mansur Duran
Int. J. Mol. Sci. 2018, 19(2), 374; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020374 - 26 Jan 2018
Cited by 41 | Viewed by 10499
Abstract
Acute ischemia of an extremity occurs in several stages, a lack of oxygen being the primary contributor of the event. Although underlying patho-mechanisms are similar, it is important to determine whether it is an acute or chronic event. Healthy tissue does not contain [...] Read more.
Acute ischemia of an extremity occurs in several stages, a lack of oxygen being the primary contributor of the event. Although underlying patho-mechanisms are similar, it is important to determine whether it is an acute or chronic event. Healthy tissue does not contain enlarged collaterals, which are formed in chronically malperfused tissue and can maintain a minimum supply despite occlusion. The underlying processes for enhanced collateral blood flow are sprouting vessels from pre-existing vessels (via angiogenesis) and a lumen extension of arterioles (via arteriogenesis). While disturbed flow patterns with associated local low shear stress upregulate angiogenesis promoting genes, elevated shear stress may trigger arteriogenesis due to increased blood volume. In case of an acute ischemia, especially during the reperfusion phase, fluid transfer occurs into the tissue while the vascular bed is simultaneously reduced and no longer reacts to vaso-relaxing factors such as nitric oxide. This process results in an exacerbative cycle, in which increased peripheral resistance leads to an additional lack of oxygen. This whole process is accompanied by an inundation of inflammatory cells, which amplify the inflammatory response by cytokine release. However, an extremity is an individual-specific composition of different tissues, so these processes may vary dramatically between patients. The image is more uniform when broken down to the single cell stage. Because each cell is dependent on energy produced from aerobic respiration, an event of acute hypoxia can be a life-threatening situation. Aerobic processes responsible for yielding adenosine triphosphate (ATP), such as the electron transport chain and oxidative phosphorylation in the mitochondria, suffer first, thus disrupting the integrity of cellular respiration. One consequence of this is irreparable damage of the cell membrane due to an imbalance of electrolytes. The eventual increase in net fluid influx associated with a decrease in intracellular pH is considered an end-stage event. Due to the lack of ATP, individual cell organelles can no longer sustain their activity, thus initiating the cascade pathways of apoptosis via the release of cytokines such as the BCL2 associated X protein (BAX). As ischemia may lead to direct necrosis, inflammatory processes are further aggravated. In the case of reperfusion, the flow of nascent oxygen will cause additional damage to the cell, further initiating apoptosis in additional surrounding cells. In particular, free oxygen radicals are formed, causing severe damage to cell membranes and desoxyribonucleic acid (DNA). However, the increased tissue stress caused by this process may be transient, as radical scavengers may attenuate the damage. Taking the above into final consideration, it is clearly elucidated that acute ischemia and subsequent reperfusion is a process that leads to acute tissue damage combined with end-organ loss of function, a condition that is difficult to counteract. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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13 pages, 769 KiB  
Review
Alpha Lipoic Acid: A Therapeutic Strategy that Tend to Limit the Action of Free Radicals in Transplantation
by Nella Ambrosi, Diego Guerrieri, Fiorella Caro, Francisco Sanchez, Geraldine Haeublein, Domingo Casadei, Claudio Incardona and Eduardo Chuluyan
Int. J. Mol. Sci. 2018, 19(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010102 - 04 Jan 2018
Cited by 29 | Viewed by 8551
Abstract
Organ replacement is an option to mitigate irreversible organ damage. This procedure has achieved a considerable degree of acceptance. However, several factors significantly limit its effectiveness. Among them, the initial inflammatory graft reaction due to ischemia-reperfusion injury (IRI) has a fundamental influence on [...] Read more.
Organ replacement is an option to mitigate irreversible organ damage. This procedure has achieved a considerable degree of acceptance. However, several factors significantly limit its effectiveness. Among them, the initial inflammatory graft reaction due to ischemia-reperfusion injury (IRI) has a fundamental influence on the short and long term organ function. The reactive oxygen species (ROS) produced during the IRI actively participates in these adverse events. Therapeutic strategies that tend to limit the action of free radicals could result in beneficial effects in transplantation outcome. Accordingly, the anti-oxidant α-lipoic acid (ALA) have been proved to be protective in several animal experimental models and humans. In a clinical trial, ALA was found to decrease hepatic IRI after hepatic occlusion and resection. Furthermore, the treatment of cadaveric donor and recipient with ALA had a protective effect in the short-term outcome in simultaneous kidney and pancreas transplanted patients. These studies support ALA as a drug to mitigate the damage caused by IRI and reinforce the knowledge about the deleterious consequences of ROS on graft injury in transplantation. The goal of this review is to overview the current knowledge about ROS in transplantation and the use of ALA to mitigate it. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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490 KiB  
Review
Proteasome and Organs Ischemia-Reperfusion Injury
by Joan Oliva
Int. J. Mol. Sci. 2018, 19(1), 106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010106 - 30 Dec 2017
Cited by 14 | Viewed by 6065
Abstract
The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by the development of organ preservation solutions. The storage of organs in preservation solutions is followed by the ischemia of [...] Read more.
The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by the development of organ preservation solutions. The storage of organs in preservation solutions is followed by the ischemia of the organ, resulting in a shortage of oxygen and nutrients, which damage the tissues. When the organ is ready for the transplantation, the reperfusion of the organ induces an increase of the oxidative stress, endoplasmic reticulum stress, and inflammation which causes tissue damage, resulting in a decrease of the transplantation success. However, the addition of proteasome inhibitor in the preservation solution alleviated the injuries due to the ischemia-reperfusion process. The proteasome is a protein structure involved in the regulation the inflammation and the clearance of damaged proteins. The goal of this review is to summarize the role of the proteasome and pharmacological compounds that regulate the proteasome in protecting the organs from the ischemia-reperfusion injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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605 KiB  
Review
Mechanisms of Acupuncture Therapy in Ischemic Stroke Rehabilitation: A Literature Review of Basic Studies
by Lina M. Chavez, Shiang-Suo Huang, Iona MacDonald, Jaung-Geng Lin, Yu-Chen Lee and Yi-Hung Chen
Int. J. Mol. Sci. 2017, 18(11), 2270; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112270 - 28 Oct 2017
Cited by 179 | Viewed by 22531
Abstract
Acupuncture is recommended by the World Health Organization (WHO) as an alternative and complementary strategy for stroke treatment and for improving stroke care. Clinical trial and meta-analysis findings have demonstrated the efficacy of acupuncture in improving balance function, reducing spasticity, and increasing muscle [...] Read more.
Acupuncture is recommended by the World Health Organization (WHO) as an alternative and complementary strategy for stroke treatment and for improving stroke care. Clinical trial and meta-analysis findings have demonstrated the efficacy of acupuncture in improving balance function, reducing spasticity, and increasing muscle strength and general well-being post-stroke. The mechanisms underlying the beneficial effects of acupuncture in stroke rehabilitation remain unclear. The aim of this study was to conduct a literature review, summarize the current known mechanisms in ischemic stroke rehabilitation through acupuncture and electroacupuncture (EA) therapy, and to detail the frequently used acupoints implicated in these effects. The evidence in this review indicates that five major different mechanisms are involved in the beneficial effects of acupuncture/EA on ischemic stroke rehabilitation: (1) Promotion of neurogenesis and cell proliferation in the central nervous system (CNS); (2) Regulation of cerebral blood flow in the ischemic area; (3) Anti-apoptosis in the ischemic area; (4) Regulation of neurochemicals; and, (5) Improvement of impaired long-term potentiation (LTP) and memory after stroke. The most frequently used acupoints in basic studies include Baihui (GV20), Zusanli (ST36), Quchi (LI11), Shuigou (GV26), Dazhui (GV14), and Hegu (LI4). Our findings show that acupuncture exerts a beneficial effect on ischemic stroke through modulation of different mechanisms originating in the CNS. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury)
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